It is well known in the art that pharmaceutically active ingredients (APIs) exhibit a wide variety of physicochemical characteristics that influence and that are relevant for e.g. the handling of the API, such as its manufacture. When manufacturing API, e.g. into final dosage forms, it is important that, on the one hand, adequate formulation characteristics are achieved, and on the other hand, that the intermediates of such formulations or final dosage forms can be adequately processed, such as in a robust, fast, and cost efficient way.
The respective physicochemical characteristics influence the segregation of the API inside the powder mixture during its movement e.g. in pipes, hopper and/or feeder of apparatus used for processing the API. Further, these characteristics influence reproducibility and content uniformity of the API in a batch or between batches, in particular in low dose formulations or direct compression processes. Also, parameters such as flowability, compressibility, cohesiveness and lubrication of the API or mixtures of API and excipients are influenced by the specific characteristics of an API and thus may be critical as to processibility in automated production.
Thus, in order to improve properties of the API which are relevant to the manufacturing process, various ways of processing the API are known in prior art. For instance, prior to incorporation of the API into a pharmaceutical formulation, the API can be subjected to several physical or physicochemical processes such as recrystallization, transformation into different polymorphic forms or transformation of the API into intermediate forms, such as solid forms like granules or particles, which may then be further processed. Processes an API can be subjected to may be the conversion of powders comprising the API to granules or particles. The conversion of powders to granules is called “granulation”. The most commonly employed granulation methods are wet-granulation, dry granulation and hot-melt granulation. The thus-obtained granules or particles can then be further processed, e.g. into dosage forms such as solid oral dosage forms.
Amongst other factors, also the respective susceptibilities of an API e.g. towards certain solvents or treatments have to be taken into account when processing it. An example of an API that is known to have challenging physical and physicochemical properties that are relevant with regard to the processibility is afatinib dimaleate: It exhibits susceptibility against moisture affecting the chemical stability of the API; the precipitated API exhibits a needle shape, causing a high variation of its poured density due to random arrangement and length of the needles; it exhibits poor flow properties due to increased resistance of the needles to align in flow direction; capping or laminating of tablets can occur during a direct compression process due to entrapment of too much air inside the final blend; it exhibits a low compressibility; it exhibits adhesive properties on surfaces; and/or finally it exhibits a random variability of its poured densities.
U.S. Pat. No. 8,545,884 B2 discloses a process comprising a step of compacting the API afatinib dimaleate for densification, followed by a sieving step, in order to provide API that is suitable for further processing.
Despite the above described process steps, there is still a need and thus an object for improved methods for preparing granules or particles comprising afatinib dimaleate, for improved granules or particles, as well as for improved dosage forms comprising said granules or particles.